Clinical Manifestations, Diagnosis, and Treatment of Active Tuberculosis
This section describes the pathophysiology, clinical manifestations, and treatment of active tuberculosis (TB) whether or not the patient developed symptoms on a primary exposure or reactivated a latent TB. If there is any indication that a patient has active TB, the patient must be treated immediately to avoid premature death and unrecognized transmission of Mycobacterium tuberculosis.3899
Primary Tuberculosis
Primary tuberculosis (TB) is the term used to describe the initial infection following exposure to TB. Reactivation may occur at a later stage and will be described later in this section.
Pathophysiology of Primary Tuberculosis
Initial tuberculosis infection (primary TB) occurs when TB-containing material is inhaled, usually when one is exposed to a TB-infected individual who is coughing or sneezing.3877
Because of the ventilatory pattern of the lungs, the TB bacilli usually lodge in the middle or lower lobes of the lung, although any lobe can become potentially infected.3877 Once lodged in the alveolus, the TB bacilli are ingested by alveolar macrophages. Often the macrophage is not able to destroy the TB bacillus, and the bacilli are able to multiply within the macrophage. Eventually the macrophage bursts, and the process begins again in new macrophages. This leads to a period of rapid growth, proliferation, and spread of TB bacilli.
Figure 887 – Transmission and Pathogenesis
Centers for Disease Control and Prevention (CDC). Transmission and Pathogenesis. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter2/trans1.htm Accessed July 11, 2009.
Some figures may not display clearly when rendered as a PDF or printed.
During this period of logarithmic growth, the bacilli spread via lymphatic channels to the hilar and mediastinal lymph nodes and into the bloodstream to various locations in the body.3877 This seeding of different sites in the body sets up foci that may reactivate in the future if conditions are right (e.g., immunosuppression).
Two to ten weeks after the infection starts,
cell-mediated immunity develops, which stops the rapid growth and
dissemination of the TB bacilli. However, this does not usually lead
to death of all the TB bacilli, and there are foci of TB bacilli that
remain under control, but alive, for years or decades—when
they may reactivate under proper conditions. Approximately 95% of
normal hosts can control the initial infection and develop acquired
resistance to it, after which time the TB remains latent; 5% of this
group will eventually reactivate extrapulmonary or pulmonary TB. The
remaining 5% of individuals will develop active TB following the initial
infection.3877 However, the odds of reactivation are much
higher in immunosuppressed individuals, including individuals treated
with anti-tumor necrosis
Clinical Manifestations of Primary Tuberculosis
Many patients are asymptomatic with primary infections or have only nonspecific symptoms such as fever, which occurs in 70%–80% of cases. Erythema nodosum may be seen in primary tuberculosis (TB) in as many as 18% of cases, according to Poulsen’s series.3876 The hallmark of chest x-ray findings in primary TB is lymphadenopathy with paratracheal, hilar, or mediastinal nodes as the most common sites.3877 Parenchymal lesions may be small at this stage and are evident in less than a third of adults with primary TB.3876 Pleural effusion occurs in 30%-35% of adults with primary TB3876 and may be the only manifestation in 5%.3877
Diagnosis of Primary Pulmonary Active Tuberculosis
Pulmonary disease is the most frequent manifestation of both primary and reactivated disease; however, extrapulmonary involvement increases in frequency with an immunocompromised host.3946 The diagnosis is typically made by demonstration of acid-fast bacilli (AFB) on a sputum smear and isolation of Mycobacterium tuberculosis from the culture of this sputum.3873 Recommendations are for the submission of at least 3 sputum specimens, preferably collected on different days.3946 Sputum induction, bronchoscopy, or gastric aspiration can be performed in individuals unable to provide a sputum sample, and infection control precautions should be followed during the collection of specimens.3880
A presumptive diagnosis of active TB is often made on the basis of microscopic examination of a stained sputum smear for AFB.
Figure 890 – AFB Smear
Centers for Disease Control and Prevention (CDC). Acid-Fast Bacilli Smear. CDC website.http://www.cdc.gov/tb/pubs/slidesets/core/default.htm. Accessed July 16, 2009.
Some figures may not display clearly when rendered as a PDF or printed.
Confirmation usually requires identification of M tuberculosis in a culture from a sputum sample. All specimens should be cultured, even if smear negative. Results are seen in 4-14 days when liquid medium systems are used.3882 For extrapulmonary disease, samples are obtained by a variety of methods, depending on the site where tuberculosis (TB) is suspected (see Clinical Manifestations of Primary Tuberculosis).
Mycobacterial culture of all clinical specimens suspected of containing M tuberculosis should be performed because culture is more sensitive than microscopy. Growth of the organism is necessary for precise species identification and because drug-susceptibility testing requires culture of the organism. The sensitivity of culture is approximately 80%-85% with a specificity of approximately 98%. Drug-susceptibility testing should be performed on all initial isolates in order to determine what therapy will constitute an effective regimen.3946
Mycobacterial cultures may take 1-8 weeks to
grow, which is often an unacceptably long period of time to confirm
a diagnosis of TB, especially if empiric therapy is not given. For
this reason nucleic acid amplification (NAA) tests (rapid diagnostic
tests) have been developed.3883 These
tests allow the identification of M tuberculosis within
3-5 hours. The tests are based on polymerase chain reaction (PCR)
of specific nucleic acid sequences found in M tuberculosis. The FDA has approved several NAA assays for use in rapid identification
of M tuberculosis complex in respiratory samples
in patients who have never received or received
Treatment of Primary Pulmonary Tuberculosis
The products described in the following sections discussing the treatment of tuberculosis are all FDA approved. In addition, infectious disease specialists and Centers for Disease Control and Prevention guidelines should be consulted for the most appropriate treatment.
Deciding to Initiate Treatment
According to the recommendations from the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America in 2003, the decision to initiate anti-tuberculosis (TB) chemotherapy should be based on multiple factors including: epidemiologic information; clinical, pathological, and radiographic findings; and microscopic examination of acid-fast bacilli (AFB)-stained sputum smears (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A tuberculin skin test (TST) may be done at the time of initial evaluation, but a negative TST should not and does not exclude the diagnosis of active TB.
If suspicion of TB is high or if the patient is seriously ill with a pulmonary or extrapulmonary disorder that is thought to be possibly TB, combination chemotherapy using one of the recommended regimens should be initiated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of TB.3886 If the diagnosis is confirmed by isolation of M tuberculosis or a positive NAA test, treatment can be continued to complete a standard course of therapy.
Treatment Regimens
The American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America have 4 recommended regimens for treating patients with active tuberculosis (TB) caused by drug-susceptible organisms. Each regimen has an initial phase of 2 months, followed by a choice of several options for the continuation phase of either 4-7 months. The recommended treatment regimens are listed below and are indicated in the treatment of HIV-negative individuals. The initial phases are denoted by a number (1, 2, 3, or 4), and the continuation phases that relate to the initial phase are denoted by the number plus a letter designation (a, b, or c).3886, 3895 Regimens are adjusted according to the results of drug-susceptibility testing.3884
Because of the relatively high proportion of adult patients with active TB caused by organisms that are resistant to isoniazid (INH), 4 drugs are necessary in the initial phase for the 6-month regimen to be maximally effective. Thus, in most circumstances, the treatment regimen for all adults should consist of a 2-month initial phase of INH, rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (see Fig.894). If drug-susceptibility test results are known and the organisms are fully susceptible, EMB need not be included.
Figure 894 – Treatment Guidelines for Culture Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms
Centers for Disease Control and Prevention (CDC); American Thoracic Society, CDC; Infectious Diseases Society of America. Treatment of tuberculosis. CDC website. http://www.cdc.gov/mmwr/pdf/rr/rr5211.pdf. MMWR Morb Mortal Wkly Rep. 2003;52(RR-11):1-77.
Some figures may not display clearly when rendered as a PDF or printed.
Treatment Toxicity
Drug-induced hepatitis, the most serious common adverse effect, is defined as a serum aspartate aminotransferase (AST) level more than 3 times the upper limit of normal (ULN) in the presence of symptoms, or more than 5 times the ULN in the absence of symptoms. If hepatitis occurs, INH, RIF, and PZA, all potential causes of hepatic injury, should be stopped immediately. Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and the patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol. Two or more anti-tuberculosis medications without hepatotoxicity, such as EMB, an aminoglycoside, or a fluoroquinolone, may be used until the cause of the hepatitis is identified. Once the AST level decreases to less than 2 times the ULN and symptoms have significantly improved, the first-line medications should be restarted in sequential fashion. Close monitoring, with repeat measurements of serum AST and bilirubin and symptom review, is essential in managing these patients.3886
In addition to hepatitis, which may be fatal, INH can also cause peripheral neurotoxicity, CNS effects, lupus-like syndrome, hypersensitivity reactions, monoamine (histamine/tyramine) poisoning, and diarrhea. 11208 Rifampin may cause hepatitis as well as cutaneous reactions, GI reactions (nausea, anorexia, abdominal pain), flu-like syndrome, severe immunologic reactions, orange discoloration of bodily fluids, and serious interactions with other drugs due to induction of hepatic microsomal enzymes. 11209 Pyrazinamide may cause hepatitis, GI symptoms such as nausea and vomiting, nongouty polyarthralgia, asymptomatic hyperuricemia, acute gouty arthritis, transient morbilliform rash, and dermatitis. 11210 Ethambutol is the only one of the four listed drugs that does not include hepatitis listed as an adverse event in the prescribing information. However, adverse reactions include retrobulbar neuritis, peripheral neuritis, and cutaneous reactions. 11211 Prednisone may cause a variety of adverse effects, including, but not limited to the following: fluid and electrolyte disturbances, musculoskeletal (e.g., muscle weakness, osteoporosis, and pathologic long bone fractures), gastrointestinal (e.g., peptic ulcer, pancreatitis), dermatologic (e.g., impaired wound healing, facial erythema, petechiae), neurologic (e.g., convulsions, vertigo, headache), endocrine (e.g., menstrual irregularities, development of cushingoid state, manifestations of latent diabetes mellitus), ophthalmic (e.g., glaucoma, exophthalmos), and metabolic (e.g., negative nitrogen balance due to protein catabolism) issues.11212
Reactivation of Pulmonary Tuberculosis
Certain conditions predispose individuals to develop reactivation—most prominently a shift in the balance between the host immune system and the tuberculosis bacilli. This shift can be caused by immunosuppressive drugs, HIV infection, malnutrition, or development of other chronic diseases (e.g., diabetes, chronic renal failure).3877
Pathophysiology of Reactivation Tuberculosis (Postprimary Tuberculosis)
The most common sites of reactivation tuberculosis (TB) by far are the upper lobes of the lung because of higher oxygen tension and poor lymphatic drainage. However, whenever TB reactivates, there is a chance of developing miliary TB in which the foci discharge into the bloodstream, releasing a large number of bacilli that embolize to capillary beds in multiple organs.3877 Other common sites of tuberculosis disease include the pleura, central nervous system, lymphatic system, genitourinary system, and the bones and joints.3887
Clinical Manifestations of Pulmonary Reactivation Tuberculosis
Many patients have only nonspecific symptoms—cough, sputum production, and less commonly, hemoptysis.3888 Cough may be productive and prolonged (lasting ≥3 weeks), with associated chest pain and hemoptysis.3889
Other nonspecific symptoms include fatigue, fever, night sweats, and weight loss. Laboratory findings are also nonspecific—most of the time they are normal3888 ; however, if abnormal, elevated white blood cell count or anemia are the most common. Hyponatremia, caused by secretion of an antidiuretic-hormone–like substance from damaged lung tissue, occurs in approximately 10% of individuals with active pulmonary tuberculosis (TB).
Reactivation disease is controlled by delayed-type cell-mediated immunity—this kills bacilli-laden macrophages but at the expense of destruction of nearby lung tissue. Therefore, control and resolution of pulmonary TB is always accompanied by some degree of lung damage. This is sometimes manifested by cavitation, which occurs in 40%-45% of cases of active pulmonary TB. Chest x-ray can show many patterns, but the most common are opacifications in the upper lobes and cavitation.3877
Figure 897 – Chest Radiograph
Centers for Disease Control and Prevention (CDC). Chest Radiograph. CDC website.http://www.cdc.gov/tb/pubs/slidesets/core/Chapter5/diag7.htm. Accessed June 30, 2009.
Some figures may not display clearly when rendered as a PDF or printed.
Without adequate treatment, some patients will have progression of the pulmonary disease to the point where the lung is destroyed, leading to permanent disability or death. Such lung destruction occurs after a long period without treatment, usually at least 6 to 7 years.3891
Diagnosis of Pulmonary Reactivation of Latent Tuberculosis
Pulmonary disease is the most frequent manifestation of both primary and reactivation disease; however, extrapulmonary involvement increases in frequency with an immunocompromised host.3946 The diagnosis is typically made by demonstration of acid-fast bacilli on a sputum smear and isolation of M tuberculosis from the culture of this sputum.3873 Recommendations are for the submission of at least 3 sputum specimens, preferably collected on different days.3873
The tuberculin skin test (TST) using purified protein derivative (PPD) is the method routinely used for identifying latent tuberculosis (TB) infection. This test is based on the development of a delayed-type hypersensitivity reaction to tubercular antigens in individuals with TB, latent or active. The standard test dose of a PPD/TST preparation is 5 tuberculin units of solution that is injected intradermally. The Mantoux (single-needle injection) method is preferable to the multiple-puncture tests. The reaction typically begins 5-6 hours after injection, and induration peaks at 48-72 hours.3956
Treatment of Pulmonary Reactivation of Latent Tuberculosis
Once reactivation of latent tuberculosis (TB) has been diagnosed or suspected as the diagnosis, the treatment follows the guidelines of active TB.
An infectious disease specialist should be consulted for the treatment of patients with TB. In addition, the Centers for Disease Control and Prevention’s web site should be reviewed for up-to-date treatment guidelines.3886
Treatment Regimens
The treatment regimen for pulmonary reactivation tuberculosis (TB) resembles that for primary pulmonary TB. Please see Treatment of Primary Pulmonary Tuberculosis.
Treatment Toxicity
Treatment toxicity, in the form of drug-induced hepatitis, and other adverse events may occur. Please see Treatment Toxicity.
Content on this page was last reviewed on August 20, 2008.
Content on this page was last changed on March 19, 2009.
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